The attention-deficit/hyperactivity disorder (hereinafter referred to as “ADHD” in some cases) is a neurodevelopmental disorder characterized by core symptoms of inattention and/or hyperactivity and impulsivity. The Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) by the American Psychiatric Association describes that the estimated prevalence of this disease is 3 to 7% of school-aged children and 2 to 4% of adults, and the male-to-female ratio of the patients is from 2:1 to 9:1. According to an epidemiologic study based on the DSM-IV, the prevalence of ADHD symptoms in Japanese school-aged children is reported to be 5.6%. Also, in ADHD, comorbidity disorders such as learning disorder, depression, Asperger's syndrome, and oppositional defiant disorder are observed. Regarding neurobiological bases, it has been reported that ADHD patients have volume differences in brain regions such as the cerebellum, the splenium of corpus callosum, the cerebral cortex, the striatum, etc. (morphological anomalies) or imbalance in monoaminergic imbalance (functional anomaly), but details of the cause of the disease are unknown.
The pathogenesis of ADHD is reported that there is a link between a neurotransmitter dopamine and ADHD (Non-Patent Document 1). In studies on genetic factors for ADHD, dopamine-related genes such as dopamine transporter has been implicated.
It has been further reported on acquired factors such as perinatal factors or family environments and on involvement of various genes other than dopamine-related genes. Nowadays, therefore, it is considered that various neurochemical factors and environmental factors, in addition to a plurality of genetic predispositions, are involved complicatedly in the pathogenesis of ADHD (Non-Patent Documents 2 and 3).
ADHD has been treated by behavioral therapy (stimulation of social development) and medication therapy (control of symptoms). At present, the drugs used for the medication therapy are largely grouped into stimulants amphetamines including amphetamine, dextroamphetamine, and lisdexamfetamine, and methylphenidate, and non-stimulants atomoxetine, guanfacine and clonidine (in Japan, methylphenidate and atomoxetine are approved by the Government in 2013). The plasma membrane monoamine transporters in the brain are molecular targets of amphetamines, methylphenidate and atomoxetine.
At present, among approved medications for ADHD, methylphenidate has the highest effects and is used as the first-choice of medication treatment. Methylphenidate has high affinity for norepinephrine (NET) and dopamine transporters (DAT), and exerts its effect rapidly on the core symptoms.
However, even methylphenidate as the first-choice of medication has many ineffective or intolerant cases: it is reported to be ineffective for approximately three out of ten ADHD patients. Also, strong central stimulation and side effects including loss of appetite, headache, and insomnia are observed. Since many of ADHD patients are school-age children, there are concerns about adverse effects such as the risk of drug dependence and abuse due to long-term dosing. Moreover, since methylphenidate has only two types of available oral tablets, i.e., the immediate-release type and the sustained-release type, it cannot be administered so as to make the therapy of behavioral inhibition disorder (BID) effective in the main part of the awake time of the patient (Patent Document 2). Amphetamines such as amphetamine, dextroamphetamine and lisdexamfetamine, which are stimulants like methylphenidate, are used for the therapy of ADHD. However, these amphetamines with high potential for abuse are drugs under strict regulatory control as stimulants, and thus difficult in handling.
Atomoxetine is administered for cases where stimulants are ineffective or for patients who have risks of dependence and abuse, a comorbidity disorder and side effects.
Atomoxetine has highly selective affinity to NET, less potential for abuse, and comparatively low incidence of serious adverse events. However, atomoxetine might result in maximum response at the dose of once or twice a day over several weeks. Also, clinical trials are suggested that the atomoxetine's efficacy [effect size as the magnitude of improvement effect based on the ADHD Rating Scale total score=(average value of drug-treated group−average value of control group)/standard deviation of control group] is weaker compared with that of methylphenidate. Atomoxetine is therefore selected for ineffective cases with stimulants, the cases where the risk of dependence/abuse is concerned, and the cases where a side effect, a comorbid disorder, etc. are concerned.
While atomoxetine can improve the ADHD symptoms and is low in the possibility of dependence formation and frequency of adverse events based on the central stimulation action, which are feared for methylphenidate, the weak efficacy and slow onset of drug efficacy form a clinical bottleneck. Moreover, although atomoxetine is considered lower frequency of adverse events than methylphenidate, adverse events still manifest with high frequency: adverse events are reported in 209 subjects out of 278 safety-evaluated subjects (75.2%) in a clinical trial for children in Japan, where common adverse events include headache (22.3%), decreased appetite (18.3%), somnolence (14.0%), abdominal pain, (12.2%), and nausea (9.7%), and in 315 subjects out of 392 safety-evaluated subjects (including 278 Japanese patients) (80.4%) in a clinical trial for Japanese and Asian adults, where main symptoms include nausea (46.9%), decreased appetite (20.9%), somnolence (16.6%), dry mouth (13.8%), and headaches (10.5%) (prescription drug package inserts). Also, in ADHD model rats or normal rats, while methylphenidate exhibits dose-dependent increases in locomotor activities, atomoxetine does not exhibit increases in locomotor activities irrespective of increases in doses, and exhibit decreases in locomotor activities during an exploration period.
Guanfacine and clonidine, which have different pharmacological actions from drugs having affinity for monoamine transporters as those described above, exert efficacies via the presynaptic and postsynaptic α2 adrenoceptor agonistic action, but their efficacies thereof in extended formulation is shown to be equivalent to that of atomoxetine. When the effects of existing ADHD medications are insufficient, mood-stabilizers, antidepressants, antipsychotics, anti-anxiety medications, etc. are prescribed according to the symptom. However, since no therapeutic algorism according to the ADHD clinical state has been made, their effects on the core symptoms are only partial.
Bupropion is one of antidepressants acting as a norepinephrine and dopamine reuptake inhibitor (NDRI), and is prescribed, as optional treatment, for an ADHD patient for whom neither methylphenidate nor atomoxetine is effective, or for a type of patient whose condition is rather worsened with methylphenidate or atomoxetine. However, in this case, also, the efficacy of improving the core symptoms of ADHD is still insufficient.